A patient came to see me recently: 62, postmenopausal, doing everything she had been told to do. Whole foods, protein and fiber with every meal, calorie restriction, intermittent fasting, HIIT, Barre. Five years of effort and her weight had continued to climb, almost entirely in her abdomen.
She had already completed a comprehensive set of labs. Her fasting glucose was 99 mg/dL, hemoglobin A1c was 5.5%, her cholesterol was mildly elevated, her hormones were consistent with the postmenopausal range, and her thyroid function was normal. Her previous providers had reviewed the results and found nothing that explained what she was experiencing. The conclusion she kept hearing was, “It’s just normal aging.”
A fasting glucose of 99 is normal. A TSH trending upward for two years is normal. Testosterone essentially undetectable on active therapy is, technically, normal. None of those findings triggered any follow-up. This is not a failure of clinical judgment. It is a failure of the questions being asked.
Most routine laboratory panels are designed to detect disease once it is already present. They are not designed to identify the subtle physiologic changes that precede it by years. The tests below ask different questions. They look for the early shifts in metabolic and hormonal health that standard screening often misses.
1. Fasting insulin
Glucose is a lagging indicator. By the time fasting glucose climbs out of range, insulin resistance has typically been building for years. Sometimes a decade. Fasting insulin catches it early, often before HbA1c moves, before glucose tips, before any of the metabolic downstream effects become visible on a standard panel.
The conventional reference range goes up to around 25 uIU/mL. I want it below 7, ideally below 5. Anything above that, in the context of abdominal weight gain that is resistant to diet and exercise, tells me we are dealing with hyperinsulinemia driving fat storage, not a willpower problem.
Insulin resistance is upstream of type 2 diabetes, cardiovascular disease, certain cancers, and cognitive decline. It is also one of the most modifiable things on this list. If you take nothing else from this piece, request this test.
When fasting insulin is elevated, there’s an intervention hierarchy. Lifestyle first: reducing refined carbohydrates and sugar, eliminating fructose and ultra-processed foods, consistent aerobic exercise, and resistance training to build muscle mass (your primary glucose disposal organ). Sleep and stress matter more than most people realize; a single night of poor sleep measurably impairs insulin sensitivity, and chronically elevated cortisol directly antagonizes insulin action. Time-restricted eating has solid mechanistic support and works well for some but not all patients.
Supplements and botanicals with evidence for improving insulin sensitivity include berberine, myo-inositol, magnesium, alpha-lipoic acid, chromium, omega-3 fatty acids, cinnamon, bitter melon, Gymnema sylvestre, apple cider vinegar, aloe vera, fenugreek, banaba leaf, resveratrol, and zinc! Berberine has the strongest data of the group.
2. ApoB + NMR LipoProfile
Standard LDL is a cholesterol concentration. It does not tell you how many atherogenic particles are in circulation or what they look like. ApoB counts the particles. The NMR LipoProfile shows their size and metabolic behavior. Together, they give you a cardiovascular risk picture that a standard lipid panel simply cannot.
Two people with identical LDL-C can have very different particle counts and very different risk profiles. Small, dense LDL particles are significantly more atherogenic than large, buoyant ones, and someone with borderline LDL but predominantly small particles is in a different situation than their cholesterol number suggests. The NMR also generates an LP-IR score, a validated insulin resistance measure derived from lipoprotein concentrations, which means you can sometimes detect metabolic dysfunction through the lipid picture before fasting insulin is even ordered.
For anyone with abdominal adiposity, a family history of early cardiovascular disease, or a metabolic syndrome picture, these are the labs that add real resolution. My patient’s triglycerides had improved significantly over three years with diet and lifestyle modifications, surprisingly LP-IR score worsened showing significant insulin resistance.
WHy? Improving triglycerides tells you the diet is working. A worsening LP-IR tells you the underlying metabolic dysfunction is not resolved and may be progressing despite all your dietary efforts. They are not contradictory findings; they are measuring different layers of the same problem.
3. Lipoprotein(a) — Lp(a)
Lp(a) is one of the strongest independent predictors of early cardiovascular disease and aortic stenosis, and about 20% of the population carries significantly elevated levels. Genetics account for roughly 70 to 90% of an individual’s baseline, which is why it is largely non-modifiable with lifestyle but that does not make the information useless.
If Lp(a) is high, it reframes the cardiovascular risk conversation entirely: how aggressively to manage every other modifiable factor, when pharmaceutical intervention becomes appropriate, and how closely to monitor. If it is normal, you can largely set it aside. One draw establishes your baseline and changes the clinical picture for years.
That said, Lp(a) is not perfectly fixed across a lifetime. It behaves as an acute phase reactant and can rise temporarily during illness or infection. Estrogen tends to lower it, which means levels can shift around menopause or with hormone therapy. Certain conditions move it in both directions i.e. nephrotic syndrome and hypothyroidism raise it, liver disease and hyperthyroidism lower it. PCSK9 inhibitors and high-dose niacin can also modestly reduce it. For most people a single baseline is sufficient; I recheck in patients going through significant hormonal transitions or new diagnoses that could affect the reading.
4. High-sensitivity C-reactive protein (hsCRP)
Chronic low-grade inflammation does not announce itself. There is no pain, no obvious sign, no moment where something clearly feels wrong. It just quietly drives atherosclerosis, degrades insulin sensitivity, accelerates tissue aging, and creates the environment cancer requires to establish itself.
hsCRP is one of the best tools available to measure inflammation. Anything above 1.0 mg/L warrants attention. Above 3.0, the cardiovascular risk data is significant and consistent. The key is trending it over time and reading it in context because elevated hsCRP in a postmenopausal woman with abdominal adiposity, joint pain, and poor sleep tells a very different story than an elevated reading in someone who just ran a marathon.
Visceral fat is not passive. It is an endocrine organ that actively secretes inflammatory cytokines. In my patient’s case, I expected hsCRP to be elevated. The weight gain was not just weight, it was a source of ongoing inflammatory signaling. If you want to quantify visceral fat directly, a DEXA scan is the most practical clinical option; it separates visceral from subcutaneous adipose tissue and gives you lean mass and bone density in the same scan.
When hsCRP is elevated, the interventions with the most consistent evidence are aerobic exercise, high-dose omega-3 fatty acids, dietary patterns that reduce refined carbohydrates and ultra-processed foods, adequate sleep, and addressing the root driver (whether that is insulin resistance, excess visceral fat, chronic infection, chronic stress or unmanaged autoimmunity). Red yeast rice, curcumin, magnesium, and resveratrol have reasonable data and low risk profiles.
5. Ferritin
Both directions matter here, and that is what makes ferritin easy to overlook.
Low ferritin causes fatigue, hair loss, cold intolerance, and cognitive fog that gets attributed to everything else like stress, perimenopause, poor sleep. It is frequently not caught because hemoglobin remains normal long after stores are depleted. Ferritin can be critically low while blood counts continue to remain within normal range… for now.
Elevated ferritin is a different problem. Even within the conventional “normal” range, a ferritin trending upward is an independent predictor of insulin resistance, non-alcoholic fatty liver disease, and metabolic syndrome. I start paying close attention above 100 in women.
Before treating an elevated ferritin, rule out secondary causes. Ferritin is an acute phase reactant, so inflammation alone can drive it up. Also consider hemochromatosis (check transferrin saturation and HFE testing when indicated), liver disease, alcohol use, and, less commonly, malignancy.
Once those are addressed or excluded, the most effective treatment for metabolically elevated ferritin is addressing the underlying insulin resistance. Reducing refined carbohydrates and fructose, limiting alcohol, losing excess visceral fat, and consistent aerobic exercise all lower ferritin meaningfully over time. I also counsel patients to avoid supplemental vitamin C with iron-containing meals as it significantly increases absorption.
If ferritin remains elevated despite metabolic optimization, IP6, curcumin, EGCG, and quercetin have iron-chelating properties and are reasonable adjuncts. When liver disease is in the picture, milk thistle belongs in the plan. It is hepatoprotective and anti-inflammatory, with evidence for reducing hepatic iron accumulation in MASLD and hemochromatosis.
For ferritin that is stubbornly elevated despite all of the above, therapeutic phlebotomy is appropriate in selected patients, with supporting evidence in metabolic dysfunction-associated steatotic liver disease.
6. SHBG — Sex Hormone Binding Globulin
SHBG is a proxy for insulin sensitivity that almost nobody orders. Low SHBG, independent of any other marker, predicts type 2 diabetes and cardiovascular events with enough consistency that some researchers have proposed it as a metabolic disease biomarker on its own.
Beyond metabolic risk, SHBG determines how much free hormone is bioavailable. When I am managing someone on testosterone, or evaluating a hormonal picture, SHBG tells me whether the hormone being produced or prescribed is actually getting to the tissues. A total testosterone that looks adequate can mask near-zero free testosterone when SHBG is high.
When SHBG is low alongside elevated insulin, abdominal adiposity, and androgen symptoms (fatigue, hair loss, low libido, difficulty building muscle) you are looking at a woman whose metabolic dysfunction and hormonal insufficiency are feeding each other. High insulin suppresses SHBG. Low SHBG leaves fewer androgens available. Low androgens worsen body composition and insulin sensitivity. The cycle is self-reinforcing, and none of the individual markers alone closes the case. Hormone optimization without metabolic intervention will underperform. Metabolic intervention without addressing androgens will leave significant symptoms on the table. Both have to move together.
7. Homocysteine
Homocysteine is an amino acid that accumulates when methylation is impaired, typically from inadequate B12, folate, or B6. Elevated levels are an independent predictor of cardiovascular disease, stroke, and dementia. The dementia data specifically is worth taking seriously: elevated homocysteine in midlife predicts cognitive decline a decade or more out.
It is also one of the more actionable markers on this list. In most cases, elevated homocysteine responds well to targeted B-vitamin support, particularly methylated forms in patients with MTHFR variants. Testing homocysteine without at least considering methylation status misses part of the picture.
This is a cheap test. The intervention, when needed, is cheap. The downstream consequences of missing it are not.
8. Free testosterone
In every woman. Every time.
Testosterone is not a male hormone that women happen to have a little of. It is central to muscle synthesis, metabolic rate, bone density, cognitive sharpness, libido, mood, and the ability to respond to exercise. When it is low — truly low, not just normalized against an age-adjusted reference range calibrated for decline — the effect on body composition is profound and almost entirely resistant to lifestyle intervention.
It’s important to look at free and total testosterone, not just total. Free testosterone reflects what the cells can actually use, and it is the number that correlates with symptoms. Specify LC/MS (liquid chromatography-mass spectrometry) methodology; immunoassay-based testosterone testing in women is notoriously inaccurate at low concentrations and will routinely underestimate or misreport levels.
My patient had been on testosterone gel for over nine months. Her total testosterone came back essentially undetectable, less than 3 ng/dL. Part of the problem was the delivery method: gels have notoriously variable transdermal absorption, and some patients simply do not absorb them reliably regardless of dose. She had been symptomatic the entire time and told nothing was wrong. I switched her to a compounded cream, which tends to achieve more consistent absorption.
9. Full thyroid panel: TSH, fT4, fT3, reverse T3, thyroid antibodies
TSH alone is not a thyroid assessment. It is a pituitary output signal, the brain’s commentary on thyroid function, not a direct measure of it. It does not tell you how much active thyroid hormone is reaching the cells.
The full picture requires free T4 (circulating hormone), free T3 (the biologically active form), and reverse T3 (the inactive form that competes with free T3 at the receptor). Someone can have a normal TSH and a flagged fT3-to-reverse T3 ratio that explains years of fatigue, cold intolerance, constipation, and weight resistance.
I add thyroid antibodies (TPO and thyroglobulin) routinely, including in patients who had negative antibodies years ago. Autoimmunity can develop at any point in life, and a clean result from five years ago does not tell you what is happening now. Hashimoto's often smolders for years before TSH moves, with antibodies rising long before the pituitary registers a problem. Early identification changes the clinical conversation: it shifts the framing from "your thyroid is borderline" to "you have an autoimmune condition we can monitor and address," which opens different treatment options and a different conversation about triggers. My patient's TSH had been trending upward over two years with no downstream labs ever ordered.
10. 25-OH Vitamin D
More than 40% of American adults are deficient. The number is higher in women, higher in postmenopausal women, and higher still in anyone carrying excess adiposity, because vitamin D is fat-soluble and gets sequestered in adipose tissue, away from the circulation where it can function.
The conventional cutoff for deficiency is below 20 ng/mL. Insufficiency is pegged at 20 to 30. I rarely consider anything below 50 acceptable for anyone with joint pain, autoimmune history, cardiovascular risk, or a history of cancer. The data on vitamin D and colorectal cancer, breast cancer, and all-cause mortality is among the most consistent in nutritional medicine.
My patient was at 27.5, despite already supplementing. When supplementation is not moving levels, the issue is usually absorption or dose. Sun rays is the absolutely best way to get Vitamin D. Beyond that always use D3 (cholecalciferol) rather than D2. D3 is more potent and sustains levels more reliably. Take it with the largest meal of the day, since vitamin D is fat-soluble and requires dietary fat for absorption. Sublingual drops can bypass gut absorption issues and work well in patients with GI compromise. For those with significant malabsorption (i.e. Crohn’s, celiac, post-bariatric surgery) intramuscular injection is sometimes the only reliable route. Abdominal adiposity specifically is a common reason supplementation underperforms: fat tissue sequesters vitamin D away from circulation, meaning heavier patients often need meaningfully higher doses to achieve the same serum level.
Two cofactors that often get overlooked: magnesium is required for vitamin D activation and conversion, and many people are deficient in both simultaneously. Supplementing D without addressing magnesium can limit the response. Vitamin K2 (MK-7 form) belongs alongside vitamin D whenever you are supplementing at therapeutic doses; it helps direct calcium to bone rather than soft tissue and is particularly important in anyone with cardiovascular risk.
A few more worth knowing about
I can’t help myself!
Uric acid is an independent cardiovascular and metabolic risk marker that most people only associate with gout. Elevated levels are present years before a first flare and track closely with insulin resistance
The omega-3 index measures EPA and DHA concentration in red blood cell membranes; below 4% is associated with meaningfully elevated cardiac mortality risk
AM cortisol gives a baseline read on HPA axis function; chronic stress physiology drives visceral adiposity, immune suppression, and bone loss in ways that show up elsewhere in the panel
Cystatin C is a more sensitive marker of early kidney function decline than creatinine, catching glomerular changes before standard eGFR moves
Lastly, for anyone with a significant stress or surgical history, DHEA-S reflects adrenal reserve and is one of the earlier hormonal markers to drop as the system ages or becomes chronically taxed.
My patient came in with five years of unexplained weight gain, a stack of normal results, and the working diagnosis of aging. She left with a hormone regimen that actually made sense for her - testosterone switched from gel to compounded cream, an estradiol patch, progesterone. Specific diet and lifestyle adjustments: stop intermittent fasting, start lifting heavy. Not because those are the right answers for everyone, but because her labs told us they were the right answers for her. She had a clear plan for improving insulin sensitivity with measurable milestones, and a DEXA order so we could stop guessing about body composition and bone health.
She had not been failing. She had been working without a map.
If any part of her story sounds familiar, bring this list to your next appointment:
fasting insulin
ApoB + NMR LipoProfile with LP-IR score
lipoprotein(a)
hsCRP
ferritin with iron and TIBC
SHBG
homocysteine
free and total testosterone LC/MS
full thyroid panel (TSH + free T4 + free T3 + reverse T3 + TPO antibodies + thyroglobulin antibodies)
25-OH vitamin D
Bonus: uric acid, omega-3 index, AM cortisol, cystatin C, DHEA-S.
Ksenia Malarkey, ND is a naturopathic physician specializing in integrative oncology, hormones, and metabolic health.
She provides medical care for Washington residents and offers global health coaching.
To schedule a free 15-minute consult, visit drkseniamalarkey.com
Wow. This article really is about someone like me. 62, Hashimotos for 12 years- which is in remission- I have cut out a lot of gluten and sugar. However, I gain every time my thyroid meds increase, I have the big middle, a bit of achy joints, sleep issues and low libido, low motivation and a history of heart disease in my family. Feeling ok not great or even good- just ok and muddling through with no motivation to do anything. I had almost given up - but after this article I will reach out to my Doctor and see if we can go down this path. I really want more energy and health.
Thank you for such a thorough article. Love that you mentioned magnesium in relation to vitamin d. I worked in a lab (oncology clinic) for years and so many people were deficient in magnesium. I always found it interesting that mg was not in the chemistry panels but an extra test to add on. Anyway, lovely article.